Neutrophil Extracellular Traps, Local IL-8 Expression, and Cytotoxic T-Lymphocyte Response in the Lungs of Patients With Fatal COVID-19

Melero, Ignacio; Villalba-Esparza, María; Recalde-Zamacona, Borja; Jiménez-Sánchez, Daniel; Teijeira, Álvaro; Argueta, Alan; García-Tobar, Laura; Álvarez-Gigli, Laura; Sainz, Cristina; García-Ros, David; Toledo, Estefanía; Abengozar-Muela, Marta; Fernández-Alonso, Mirian; Rodríguez-Mateos, Mariano; Reina, Gabriel; Carmona-Torre, Francisco; Quiroga, Jorge; Pozo, J.L. del; Cross, Amy; López-Janeiro, Álvaro; Hardisson, David; Echeveste, José; Lozano, María Dolores; Ho, Ling-Pei; Klenerman, Paul; Issa, Fadi; Landecho, Manuel F.; Andrea, Carlos de

doi:10.1016/j.chest.2022.06.007

Cited by 32 publications

(36 citation statements)

References 35 publications

(55 reference statements)

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“…1. Conditional Sars-cove-2 antigen induced elevation of neutrophil inhibitory and/or stimulatory cytokines [29]. 2.…”

Section: Neutrophil Immune Deviation In Covid-19mentioning

confidence: 99%

“…This opinion tempts to make showcase analysis for covid-19 in childhood [8] and in adulthood [9,10,20,29,30] aiming to deduce if any evidence for the immune deviation of neutrophil in this disease. The disease in both disease groups showed the following immune mechanisms;…”

Section: Neutrophil Immune Deviation In Covid-19mentioning

confidence: 99%

“…4. Inhibition of adaptive T cell response in continuum with enhancement of innate cellular immune responses [29],and elevation of IgG spike specific antibodies [8,10]. 5.…”

Section: Neutrophil Immune Deviation In Covid-19mentioning

confidence: 99%

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The Immune Features of Neutrophil and Neutrophil Immune Deviation Induced by Human SARS-COV-2 Infections

Shnawa

2022

JPRI

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Current published scientific works on human neutrophils have shown them to be heterogeneous in their immune functions. Activated neutrophil perform both up regulation and down regulation processes on other immune cells finalized by either tissue protection or tissue damage in virus human diseases. The objectives of the present opinion were to; I - make a show case analysis for the immune activities of neutrophil compartment both in children and adults with coviod-19 illness and ii - to deduce the possible existence of immune deviation mechanisms in this disease .The absolute numbers of circulating neutrophils in childhood and adulthood patients with sars-cov-2 infection were correlated with the infection severity .It was apparent that there was inhibition of T cell mediated immune responses with an elevated sars-cov-2 anti-spike antibodies in continuum with activated immature neutrophil phenotypes that might be induced by the virus antigens and can either preserve or damage the affected tissue. The antibody may directly inhibit T cells or activate neutrophil phenotype to inhibit T cell responses. The features of this immune deviation are; i – Conditional, ii – reversible, iii – associated with active functional state, iv – the virus antigen induced chemokine that orchestrate neutrophil and induce hyper-cytokinemia, v – acquisition of molecular surface markers variation and appearance of inhibitory markers, vi – the neutrophil/lymphocyte ration dis-proportionated, vii – activation consequences leaves tissue pathology at most, and viii – The inflammatory circuit stages may serve drug target identification and development. Thus the opinion suggest that the absolute number of circulating neutrophils is correlated with disease severity and the existence of neutrophil immune deviation in covid-19 human disease.

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“…1. Conditional Sars-cove-2 antigen induced elevation of neutrophil inhibitory and/or stimulatory cytokines [29]. 2.…”

Section: Neutrophil Immune Deviation In Covid-19mentioning

confidence: 99%

Section: Neutrophil Immune Deviation In Covid-19mentioning

confidence: 99%

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The Immune Features of Neutrophil and Neutrophil Immune Deviation Induced by Human SARS-COV-2 Infections

Shnawa

2022

JPRI

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“…/2022 We started by examining formalin-fixed paraffin-embedded (FFPE) lung sections from a cohort patients who died from PCR-positive COVID-19 pneumonitis from one hospital (University of Navarra, Spain) (n=12). Samples were obtained at the point of death and fixed immediately, markedly reducing post-mortem tissue deterioration (Melero et al, 2022). All samples were collected during the first wave of the pandemic in 2020, before vaccination and repeat infection with SARS-CoV-2.…”

Section: (Which Was Not Certified By Peer Review) Preprintmentioning

confidence: 99%

“…Re-examining the number of NETS per lung section, we observed widespread presence with no significant difference between the three histopathology states (Figure S3C). As NETS production is a feature of mature rather than immature neutrophils (Melero et al, 2022), one explanation is that there is a CD8-directed immature neutrophil localisation to proliferating alveolar epithelium, which is separate from the relatively less discriminate NETS expression by mature neutrophils.…”

Section: Tmmentioning

confidence: 99%

Unbiased single cell spatial analysis localises inflammatory clusters of immature neutrophils-CD8 T cells to alveolar progenitor cells in fatal COVID-19 lungs

Weeratunga

Denney

Bull

et al. 2022

Preprint

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Single cell spatial interrogation of the immune-structural interactions in COVID -19 lungs is challenging, mainly because of the marked cellular infiltrate and architecturally distorted microstructure. To address this, we developed a suite of mathematical tools to search for statistically significant co-locations amongst immune and structural cells identified using 37-plex imaging mass cytometry. This unbiased method revealed a cellular map interleaved with an inflammatory network of immature neutrophils, cytotoxic CD8 T cells, megakaryocytes and monocytes co-located with regenerating alveolar progenitors and endothelium. Of note, a highly active cluster of immature neutrophils and cytotoxic CD8 T cells, was found spatially linked with alveolar progenitor cells, and temporally with the diffuse alveolar damage stage. These findings provide new insights into how immune cells interact in the lungs of severe COVID-19 disease. We provide our pipeline [Spatial Omics Oxford Pipeline (SpOOx)] and visual-analytical tool, Multi-Dimensional Viewer (MDV) software, as a resource for spatial analysis.

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Efficacy and Safety of Reparixin in Patients with Severe COVID-19 Pneumonia: A Phase 3, Randomized, Double-Blind Placebo-Controlled Study

Piemonti,

Landoni,

Voza

et al. 2023

Infect Dis Ther

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Introduction Polymorphonuclear cell influx into the interstitial and bronchoalveolar spaces is a cardinal feature of severe coronavirus disease 2019 (COVID-19), principally mediated by interleukin-8 (IL-8). We sought to determine whether reparixin, a novel IL-8 pathway inhibitor, could reduce disease progression in patients hospitalized with severe COVID-19 pneumonia. Methods In this Phase 3, randomized, double-blind, placebo-controlled, multicenter study, hospitalized adult patients with severe COVID-19 pneumonia were randomized 2:1 to receive oral reparixin 1200 mg three times daily or placebo for up to 21 days or until hospital discharge. The primary endpoint was the proportion of patients alive and free of respiratory failure at Day 28, with key secondary endpoints being the proportion of patients free of respiratory failure at Day 60, incidence of intensive care unit (ICU) admission by Day 28 and time to recovery by Day 28. Results Of 279 patients randomized, 182 received at least one dose of reparixin and 88 received placebo. The proportion of patients alive and free of respiratory failure at Day 28 was similar in the two groups {83.5% versus 80.7%; odds ratio 1.63 [95% confidence interval (CI) 0.75, 3.51]; p = 0.216}. There were no statistically significant differences in the key secondary endpoints, but a numerically higher proportion of patients in the reparixin group were alive and free of respiratory failure at Day 60 (88.7% versus 84.6%; p = 0.195), fewer required ICU admissions by Day 28 (15.8% versus 21.7%; p = 0.168), and a higher proportion recovered by Day 28 compared with placebo (81.6% versus 74.9%; p = 0.167). Fewer patients experienced adverse events with reparixin than placebo (45.6% versus 54.5%), most mild or moderate intensity and not related to study treatment. Conclusions This trial did not meet the primary efficacy endpoints, yet reparixin showed a trend toward limiting disease progression as an add-on therapy in COVID-19 severe pneumonia and was well tolerated. Trial Registration ClinicalTrials.gov: NCT04878055, EudraCT: 2020-005919-51. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s40121-023-00871-5.

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Neutrophil Extracellular Traps, Local IL-8 Expression, and Cytotoxic T-Lymphocyte Response in the Lungs of Patients With Fatal COVID-19

Cited by 32 publications

References 35 publications

The Immune Features of Neutrophil and Neutrophil Immune Deviation Induced by Human SARS-COV-2 Infections

The Immune Features of Neutrophil and Neutrophil Immune Deviation Induced by Human SARS-COV-2 Infections

Unbiased single cell spatial analysis localises inflammatory clusters of immature neutrophils-CD8 T cells to alveolar progenitor cells in fatal COVID-19 lungs

Efficacy and Safety of Reparixin in Patients with Severe COVID-19 Pneumonia: A Phase 3, Randomized, Double-Blind Placebo-Controlled Study

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